Neurons communicate with each other in the brain through specialized junctions, called synapses. Drugs of abuse can change synapse structure and function together with behavioral responses related to addiction. Select molecules induce and organize synapses in the developing brain, but their functional roles during the response to drugs of abuse have not been tested. Such roles can be hypothesized based on the morphological changes of synapses in addiction as well as due to human genetic studies. One class of proteins that organize synapses are SynCAMs (also named nectin-like molecules), a family of adhesion molecules that connect pre- and postsynaptic sites. SynCAM 1 induces new, fully functional excitatory synapses in the developing brain and its expression regulates learning and memory. The objective of this application is to define to which extent the synapse-organizing protein SynCAM 1 controls synapse number and structure in brain regions affected by drugs of abuse, and how its functions impact behavioral responses to the psychostimulant cocaine. The central hypothesis of this application is that differences in synapse organization in brain regions affected by addictive drugs impact drug susceptibility, and that these drugs alter synaptogenic pathways. To attain the objective of this application, two specific aims will be pursued. The first aim of this application is to analyze whether synapse organization by SynCAM 1 impacts synapses in the nucleus accumbens and the addiction-related behaviors to which this region contributes. Second, it will be tested how altered synapse organization in the habenula, a brain region involved in reward learning, affects responses to drugs of abuse. These experiments involve the morphometric analysis of spines, the postsynaptic elements of excitatory synapses, in brain regions affected by drugs of abuse. Biochemical studies will determine effects of addictive drugs on the expression of synapse organizing proteins. Functional analyses will be performed using assays of addiction-related behaviors. In addition, a transgenic mouse model will be developed to target excitatory synaptic connectivity in the habenula. Achieving these goals is important for human health, as this application will test to which extent altered synapse organization affects the re-wiring of neuronal circuits during addiction. In summary, this application aims to identify the molecular interactions involved in synapse organization during the first response to drugs of abuse and the subsequent development of addiction. The progress under this application will allow testing to which extent differences in synapse-organizing processes predict vulnerability to drugs of abuse and whether these pathways represent novel points of therapeutic intervention. PUBLIC HEALTH RELEVANCE: Nerve cells in the brain communicate with each other through specialized junctions, called synapses. Changes in synapse formation and function impair the wiring of the brain and can contribute to neurological and behavioral dysfunction, including addiction to drugs of abuse. This research program is relevant to public health because it will analyze how addictive drugs alter the way nerve cells connect with each other, allowing us to understand what steps go wrong when substances are abused.